JPH05221965A - Beta-lactam compound and its production - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an intermediate for synthesizing penam, penem, or cephem antibiotics. CONSTITUTION:The objective compound of formula I [R<1> is H, halogen or (protected) amino; R<2> is H, halogen, lower alkoxy, lower acyl, (substituted) lower alkyl, etc.; R<3> is H or carboxyl-protecting group; R<4> is (substituted) aryl; R<5> is 2-6C alkyl, (substituted) alkynyl, (substituted) aryl or (substituted) nitrogen- contg. aromatic heterocycle], e.g. a compound of formula II. The compound of the formula I can be obtained by reaction of an azetidinone derivative of formula III [R<6> is F, (substituted) lower alkyl or (substituted) aryl] with an organotin compound of formula IV (R<7> is lower alkyl) in the presence of a palladium catalyst.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel β-lactam compound and a method for producing the same.

[0002]

DISCLOSURE OF THE INVENTION The β-lactam compound of the present invention is a novel compound which has not been described in the literature and is represented by the following general formula (1).

[0003]

[Chemical 3]

[In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group,
A lower alkyl group, a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent, a hydroxyl group or a protected hydroxyl group. R ¹ and R ² may together represent a group = 0. R ³ represents a hydrogen atom or a carboxylic acid protecting group. R ⁴ represents an aryl group which may have a substituent. R ⁵ represents a C _2-6 alkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent or a substituent. The nitrogen-containing aromatic heterocyclic group which may be possessed is shown. The β-lactam compound represented by the general formula (1) is an important intermediate for synthesizing a penam-type, penem-type, or cephem-type antibiotic as shown below, for example.

Each group shown in the present specification is specifically as follows. In the following description, unless otherwise specified, the halogen atom is fluorine, chlorine, bromine,
It means iodine atom. The lower alkyl group is, for example,
It means a linear or branched C ₁ -C ₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl group.
The aryl group means, for example, a phenyl group or a naphthyl group.

Examples of the protected amino group represented by R ¹ include phenoxyacetamide, p-methylphenoxyacetamide, p-methoxyphenoxyacetamide, p-chlorophenoxyacetamide, p-bromophenoxyacetamide, phenylacetamide, p-methyl. Phenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-bromophenylacetamide, phenylmonochloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, phenylacetoxyacetamide,
α-oxophenylacetamide, thienylacetamide, benzamide, p-methylbenzamide, pt-
Butylbenzamide, p-methoxybenzamide, p-
Chlorobenzamide, p-bromobenzamide, or
Theodora W. Greene's Protective Groups in Organic Synthesis
No. 7 of Organic Synthesis ”
The groups described in Chapter (pages 218 to 287), or protected phenylglycylamide and amino groups of phenylglycylamide, p-hydroxyphenylglycylamide and amino groups, hydroxyl groups or both. Another example is p-hydroxyphenylglycylamide.
Examples of the protecting group for the amino group of phenylglycylamide and p-hydroxyphenylglycylamide include the groups described in Chapter 7 (pages 218 to 287) of the above literature. Further, as a protective group for the hydroxyl group of p-hydroxyphenylglycylamide, refer to Chapter 2 (Chapter 10) of the above-mentioned document.
Up to page 72).

The lower alkoxy group represented by R ² is, for example, a straight or branched chain such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. C ₁ ~
An example is a C ₄ alkoxy group.

Examples of the lower acyl group represented by R ² include linear or branched C ₁ -C ₄ acyl groups such as formyl, acetyl, propionyl, butyryl and isobutyryl.

[0009] As the protected hydroxyl group, and the protecting group of the protected hydroxyl group represented by R ² lower alkyl group having a hydroxyl group or protected hydroxyl group as a substituent represented by R ^2, Chapter 2, supra Various groups described in (pages 10 to 72) can be exemplified. The substituted lower alkyl group represented by R ² is the same or different kind of substituent selected from a hydroxyl group or a protected hydroxyl group shown above, and may be substituted on the same or different carbons by one or more. Good.

The protecting group for carboxylic acid represented by R ³ is benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group, trichloroethyl group,
tert-butyl group or Chapter 5 of the above literature (Chapter 152-1
The groups described on page 92) can be exemplified.

The kind of the substituent which may be substituted on the aryl group represented by R ⁴ includes a halogen atom, a hydroxyl group,
Represented by a nitro group, a cyano group, an aryl group, a lower alkyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a mercapto group, a group R ⁸ S- (R ⁸ is a lower alkyl group or an aryl group) Alkylthio group or arylthio group, formyloxy group, group R ⁸ COO-
An acyloxy group represented by (R ⁸ is the same as the above), a formyl group, an acyl group represented by a group R ⁸ CO— (R ⁸ is the same as the above), and a group R ⁸ O— (R ⁸ is the same as the above) Examples thereof include an alkoxy group or an aryloxy group represented, a carboxyl group, an alkoxycarbonyl group represented by the group R ⁸ OCO— (R ⁸ is the same as the above), an aryloxycarbonyl group, and the like. The aryl group for R ⁴ may be substituted with one or more substituents of the same or different types selected from the above substituents.

Examples of the alkenyl group which may have a substituent represented by R ⁵ include vinyl,
1-propenyl, 2-propenyl, 1-butenyl, 2-
Examples thereof include butenyl, allyl, 1-cyclohexenyl group and the like. Examples of the alkynyl group of the alkynyl group which may have a substituent represented by R ⁵ include ethynyl and 1-
Examples include propynyl and 1-butynyl groups. Examples of the nitrogen-containing aromatic heterocyclic group represented by R ⁵ which may have a substituent include, for example, thiazole-
2-yl, thiadiazol-2-yl, benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl, imidazol-2-yl, benzimidazol-2-yl, pyramidinyl, pyridyl group and the like. Be done. Alkenyl groups represented by these R ^5, the alkynyl group, an aryl group or a nitrogen-containing aromatic heterocycle substituted and each may be a substituent group include the same substituent as substituent in R ^4. The alkenyl group, alkynyl group, aryl group or nitrogen-containing aromatic heterocyclic group for R ⁵ is substituted with one or more substituents of the same or different type selected from the above substituents on the same or different carbons. It may have been done.

Examples of the substituent which may be substituted on the lower alkyl group or aryl group represented by R ⁶ include the same substituents as those described above for R ⁴ . The lower alkyl group or aryl group for R ⁶ is one or more substituents of the same or different types selected from the above substituents,
There may be one or more substitutions on the same or different carbons.

The compound of the present invention represented by the above general formula (1) is, for example, a compound represented by the general formula

[0015]

[Chemical 4]

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ⁶ represents a fluorine atom, a lower alkyl group which may have a substituent or an aryl group which may have a substituent. The presence of a palladium catalyst azetidinone derivative represented by] the general formula _{^{(R 7) 3 -Sn-R}} 5 (3) [wherein R ⁷ represents a lower alkyl group. R ⁵ is the same as above. ] It can manufacture by making it react with the organotin compound represented by these.

In the present invention, the azetidinone derivative represented by the general formula (2) used as a starting material is produced, for example, according to the method described in JP-A-61-165367.

In producing the compound of the general formula (1) of the present invention, the organotin compound represented by the general formula (3) is prepared by reacting the compound of the general formula (2) in a suitable solvent in the presence of a palladium catalyst. React with.

Specific examples of the organotin compound represented by the general formula (3) include tetraethyltin, tetrabutyltin, vinyltributyltin, (Z) -1-propenyltributyltin and 1- (tributylstannyl) -2.
-Methylprop-1-pen, (trifluorovinyl) tributyltin, 1- (tributylstannyl) -1-propyne, (p-methoxyphenyl) tributyltin, 1-methyl-2- (tributylstannyl) pyrrole, (4- t
-Butyl-1-cyclohexen-1-yl) trimethyltin, (4-t-butyl-1-cyclohexen-1-yl) tributyltin, (E) -1,2-bis (tributylstannyl) ethylene, [p- (Trifluoromethyl) phenyl] tributyltin, vinyltributyltin, 1-
Examples thereof include methoxy-1- (tributylstannyl) ethylene, aryltributyltin, ethynyltributyltin, (phenylethynyl) tributyltin and the like. The amount of the organotin compound represented by the general formula (3) used is usually about 1 to 3 times, preferably about 1 to 2 times the mol of the compound of the general formula (2).

Examples of the palladium catalyst include palladium acetate, palladium chloride, palladium bromide, palladium iodide, palladium nitrate, palladium sulfate, palladium acetoacetate, palladium oxide, bis (acetonitrile) palladium dichloride, bis (phenylacetonitrile) dichloride. Divalent palladium salts such as palladium chloride and bis (triphenylphosphine) palladium chloride, tetrakis (triphenylphosphine) palladium, tetrakis (tri-2-furylphosphine) palladium, tetrakis (tri-2-thienylphosphine) palladium, tris Examples thereof include zero-valent palladium such as (dibenzylideneacetonyl) bispalladium, tris (dibenzylideneacetone) dipalladium, and bis (dibenzylideneacetone) palladium. The amount of these palladium catalysts used is 0. 0 with respect to the azetidinone derivative of the general formula (2).
The amount is preferably about 1 to 1 times mol, more preferably about 0.01 to 0.5 times mol.

As the solvent, any conventionally known solvent can be widely used as long as it dissolves the compound of the general formula (2) and is inactive under the reaction conditions, for example, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane. , Propylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as Freon, tetrahydrofuran,
Cyclic ethers such as dioxane, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, amides such as dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, etc. These can be used, and these are used alone or in combination of two or more. The amount of these solvents used is the compound 1k of the general formula (2).
Usually about 0.5 to 200 l, preferably 1 to 50 per g
It is preferable to set it to about l.

The above reaction is usually carried out at -60 to 100 ° C., preferably -50 to 50 ° C., and the reaction time is generally about 0.1 to 24 hours.

The azetidinone derivative of the general formula (1) thus obtained can be obtained as a substantially pure product by performing ordinary extraction operation, crystallization operation, etc. after the reaction is completed, but it can also be obtained by other methods. Of course, it can be purified.

General formula

[0025]

[Chemical 5]

[In the formula, R ¹ , R ² and R ³ are the same as defined above. The 2-exomethylenecephem derivative represented by the formula: is a compound represented by the above general formula R ⁵ SO ₂ M (5) in an organic solvent suitable for the azetinone derivative represented by the general formula (1) in which R ⁵ is a vinyl group. R5 is the same as above. M represents a metal atom. ] By reacting a nucleophile represented by the general formula

[0027]

[Chemical 6]

[In the formula, R ¹ , R ² , R ³ and R ⁵ are the same as defined above. ] It is also produced by obtaining a 2-substituted methyl-3-cephem compound represented by the following, and then reacting the obtained 2-substituted methyl-3-cephem compound with a base.

The ratio of the azetidinone derivative of the general formula (1) to the nucleophile of the general formula (5) is usually about 1 to 3 equivalents of the former, preferably 1 to 1.5.
It is recommended to use the equivalent amount. The reaction is carried out in a suitable organic solvent. Here, the organic solvent is represented by the general formula (1)
As long as it dissolves the azetidinone derivative represented by and is inert to the reaction, conventionally known compounds can be widely used, for example, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, Butyl acetate, methyl propionate, lower alkyl esters of lower carboxylic acids such as ethyl propionate, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether,
Dibutyl ether, methyl cellosolve, ethers such as dimethoxyethane, tetrahydrofuran, cyclic ethers such as dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, benzene, toluene, xylene,
Substituted or unsubstituted aromatic hydrocarbons such as chlorobenzene and anisole, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, propylene dichloride and carbon tetrachloride, and aliphatic hydrocarbons such as pentane, hexane, heptane and octane , Cyclopentane,
Examples thereof include cycloalkanes such as cyclohexane, cycloheptane and cyclooctane, amides such as dimethylformamide and dimethylacetamide, and dimethyl sulfoxide. In the present invention, these solvents may be used alone or in combination of two or more. In addition, these solvents include
Water may be contained if necessary. The amount of these solvents used is usually 0.1 per 1 kg of the compound of the general formula (1).
About 5 to 200 l, preferably about 1 to 50 l is used. The reaction is -70 to 180 ° C, preferably-
It is carried out in the range of 50 to 120 ° C., and the reaction time is generally about 0.5 to 30 hours.

In the present invention, the 2-substituted methyl-3-cephem compound represented by the general formula (6) can be isolated during the reaction by a conventional extraction and purification method. Can also be continued. Here, as the base, for example, aliphatic amine and aromatic amine can be preferably used. As a concrete example,
Triethylamine, diisopropylamine, ethyldiisopropylamine, tributylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8
-Diazabicyclo [5.4.0] undecene-7 (DB
U), 1,4-diazabicyclo [2.2.2] octane (DABCO), piperidine, N-methylpiperidine,
Examples include 2,2,6,6-tetramethylpiperidine, morpholine, N-methylmorpholine, N, N-dimethylaniline, N, N-dimethylaminopyridine and the like.
These may be used alone or in combination of two or more. The amount of these bases used is about 1 to 10 equivalents, preferably about 1 to 5 equivalents, relative to the 2-substituted methyl-3-cephem compound represented by the general formula (6). The reaction is -70 to 180 ° C, preferably -5
The reaction time is generally 0.
It is about 1 to 30 hours.

Further, particularly when it is not necessary to isolate the 2-substituted methyl-3-cephem compound represented by the general formula (6),
The nucleophilic agent of the general formula (5) and the base may be simultaneously acted on the azetinone derivative of the general formula (1) from the beginning of the reaction. In this case, it is sufficient to use the nucleophile in an amount of usually 0.001 to 2.0 equivalents, preferably 0.001 to 1.5 equivalents, relative to the compound of the general formula (1).

[0032]

INDUSTRIAL APPLICABILITY The present invention provides a novel β-lactam compound useful as a synthetic intermediate for cephem antibiotics.

[0033]

The present invention will be further clarified with reference to the following examples and reference examples.

Example 1

[0035]

[Chemical 7]

R ¹ = phenylacetamide, R ² = H,
R ³ = p-methoxybenzyl, R ⁴ = phenyl, R ⁶ =
A compound of general formula (2) (hereinafter referred to as “compound (2a)”) (100 mg) that is trifluoromethyl and palladium acetate (6.1 mg) was weighed out, dried under reduced pressure, and then replaced with nitrogen. N-methylpyrrolidinone (1 ml)
Was added to make a uniform solution, and then vinyltributyltin (60
μl) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was transferred to a separating funnel using ethyl acetate and washed with water and saturated saline. It was then dried (Na ₂ SO ₄ ) and concentrated to give a crude product. This product was purified by column chromatography to obtain R ¹ = phenylacetamide, R ^1
A compound of the general formula (1) in which ² = H, R ³ = p-methoxybenzyl, and R ⁴ = phenyl (hereinafter referred to as “compound (1a)”).
(59.7 mg, yield 72%) was obtained.

NMR (CDCl ₃ ): δppm; 2.0
5 (s, 3H), 3.66 (ABq, 2H, J = 16.
7 Hz), 3.81 (s, 3H), 4.71 (dd, 1)
H, J = 7.3 Hz, 5.4 Hz), 5.03 and 5.
16 (ABq, 2H, J = 11.9 Hz), 5.49
(D, 1H, J = 11.3 Hz), 5.64 (d, 1
H, J = 17.3 Hz), 5.81 (d, 1H, J =
5.4 Hz), 5.92 (d, 1H, J = 7.3H)
z), 7.52 (dd, 1H, J = 17.3 Hz, 1
1.3 Hz), 6.90-7.74 (m, 14H).

Example 2 In Example 1, instead of vinyltributyltin, 2-tributyltin was used.
The reaction was carried out for 22 hours using propenyltributyltin, R ¹ = phenylacetamide, R ² = H, R ³ = p
-Methoxybenzyl, R ⁴ = phenyl, R ⁵ = 2-propenyl, the compound of the general formula (1) (hereinafter referred to as “compound (1
b) ”) was obtained with a yield of 50%.

NMR (CDCl ₃ ): δ ppm; 1.7
8 (d, 3H, J = 1.5 Hz), 2.06 (s, 3
H), 3.60 and 3.64 (ABq, 2H, J = 1
7.7 Hz), 3.80 (s, 3H), 4.58 (d,
1H, J = 1.5 Hz), 4.76 (dd, 1H, J =
1.5Hz, 1.5Hz), 4.86 (dd, 1H, J
= 7.4 Hz, 5.2 Hz), 4.99 and 5.04
(ABq, 2H, J = 11.9 Hz), 5.83 (d,
1H, 5.2 Hz), 5.99 (d, 1H, J = 7.4)
Hz, NH), 6.87-7.76 (m, 14H).

Example 3 In Example 1, 2-tributyltin was used instead of 2-
Reaction was carried out for 24 hours using methyl-1-propenyltributyltin, R ¹ = phenylacetamide, R ² =
H, R ³ = p-methoxybenzyl, R ⁴ = phenyl, R
20% yield of the compound of the general formula (1) in which ⁵ = 2-methyl-1-propenyl (hereinafter referred to as "compound (1c)").
Obtained in.

NMR (CDCl ₃ ): δppm; 1.5
7 (s, 3H), 1.74 (s, 3H), 2.06
(S, 3H), 3.58 and 3.65 (ABq, 2H,
J = 22.0 Hz), 3.81 (s, 3H), 4.81
(Dd, 1H, J = 7.2 Hz, 5.2 Hz), 4.9
7 and 5.10 (ABq, 2H, J = 11.9 Hz),
5.83 (d, 1H, 5.2Hz), 5.91 (d, 1
H, J = 7.2 Hz), 6.09 (s, 1H), 6.9
8-7.73 (m, 14H).

Example 4 In Example 3, the reaction was carried out for 24 hours using tris (dibenzylideneacetone) dipalladium instead of palladium acetate as the palladium catalyst, and the compound (1c) was obtained in a yield of 67%. The NMR spectrum of this product was completely in agreement with that of the compound (1c) obtained in Example 3.

Example 5

[0044]

[Chemical 8]

A compound of the general formula (2) in which R ¹ = R ² = H, R ³ = diphenylmethyl, R ⁴ = phenyl and R ⁶ = trifluoromethyl (hereinafter referred to as “compound (2b)”) (391 mg) And palladium acetate (27.4m
N-Methylpyrrolidinone (4 ml) was added to g) and the mixture was stirred, and vinyltributyltin (268 μl) was added. After stirring at room temperature for 1 hour, the mixture was extracted with an ethyl acetate-potassium fluoride aqueous solution and washed with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residual liquid was purified by column chromatography to obtain R ¹ = R ² = H, R ³ =
General formula (1) in which diphenylmethyl and R ⁴ = phenyl
Compound (hereinafter referred to as “compound (1d)”) (250 m
g, yield 79%) was obtained.

NMR (CDCl ₃ ): δ ppm; 1.9
2 (s, 3H), 3.01 (dd, 1H, J = 2.8H
z, 15.9 Hz), 3.52 (dd, 1H, J = 5.
6 Hz, 15.9 Hz), 5.49 (dd, 1H, J =
0.9 Hz, 12.1 Hz), 5.58 (dd, 1H,
J = 2.8 Hz, 5.6 Hz,) 5.64 (dd, 1
H, J = 0.9 Hz, 16.2 Hz), 6.93 (s,
1H), 7.25-7.63 (m, 16H).

Reference Example 1

[0048]

[Chemical 9]

The compound (1d) (30.4 mg) and sodium benzenesulfinate (12 mg) were weighed, dimethylformamide (0.3 ml) was added, and the mixture was stirred.
After stirring for 1 hour, the reaction solution was extracted with ethyl acetate-water and washed twice with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residual liquid was directly used in the next reaction.
Dimethylformamide (0.3 ml) was added to the residue and the mixture was stirred at room temperature with diisopropylethylamine (40.8 μm).
l) was added. Ethyl acetate-
It was extracted with water. It was washed twice with water and dried over sodium sulfate. When the solvent was distilled off under reduced pressure and the residual liquid was purified by column chromatography, a compound of the general formula (4) in which R ¹ = R ² = H and R ³ = diphenylmethyl (hereinafter referred to as “compound (4a)” (17 0.8 mg, 81%) is obtained.

NMR (CDCl ₃ ): δppm; 2.0
7 (s, 3H), 2.97 (dd, 1H, J = 2.2H
z, 15.6 Hz), 3.59 (dd, 1H, J = 4.
8 Hz, 15.6 Hz), 4.80 (dd, 1H, J =
2.2 Hz, 4.8 Hz), 5.53 (s, 1H),
5.74 (s, 1H), 7.02 (s, 1H), 7.2
5-7.48 (m, 10H).

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] June 18, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0026

[Correction method] Change

[Correction content]

[Wherein R ¹ , R ² and R ³ are the same as defined above. 2-exomethylene cephem derivatives represented by] in a suitable organic solvent to Azechinon derivative represented by the general formula R ⁵ is a vinyl group (1), one general formula [In the formula, R ⁹ represents an aryl group which may have a substituent.
You M represents a metal atom. ] By reacting a nucleophile represented by the general formula

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0027

[Correction method] Change

[Correction content]

[0027]

[Chemical 6]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction content]

[In the formula, R ¹ , R ² , R ³ and R ⁹ are the same as defined above. Give represented by 2-substituted-3-cephem compound], then manufacturing by the exerting a base to 2-substituted-3-cephem compounds obtained.
Substitution that may be substituted on the aryl group represented by R ⁹
Examples of the group include the same substituents as the substituents for R ⁴ .
it can. The aryl group represented by R ⁹ can be any of the above substituents.
The same or different substituents selected may be the same or different.
1 or more may be substituted on the carbon.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0036

[Correction method] Change

[Correction content]

R ¹ = phenylacetamide, R ² = H,
R ³ = p-methoxybenzyl, R ⁴ = phenyl, R ⁶ =
A compound of general formula (2) (hereinafter referred to as “compound (2a)”) (100 mg) that is trifluoromethyl and palladium acetate (6.1 mg) was weighed out, dried under reduced pressure, and then replaced with nitrogen. N-methylpyrrolidinone (1 ml)
Was added to make a uniform solution, and then vinyltributyltin (60
μl) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was transferred to a separating funnel using ethyl acetate and washed with water and saturated saline. It was then dried (Na ₂ SO ₄ ) and concentrated to give a crude product. When this product was purified by column chromatography, R ¹ = phenylacetamide, R ^1
2 = ^H, R 3 = p- methoxybenzyl, ^{R 4} = phenylene <br/> Le, compounds of ^{R 5} = formula vinyl (1) (hereinafter "Compound (1a)" hereinafter) (59.7 mg, Yield 72
%)was gotten.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Name of item to be corrected] 0045

[Correction method] Change

[Correction content]

A compound of the general formula (2) in which R ¹ = R ² = H, R ³ = diphenylmethyl, R ⁴ = phenyl and R ⁶ = trifluoromethyl (hereinafter referred to as “compound (2b)”) (391 mg) And palladium acetate (27.4m
N-Methylpyrrolidinone (4 ml) was added to g) and the mixture was stirred, and vinyltributyltin (268 μl) was added. After stirring at room temperature for 1 hour, the mixture was extracted with an ethyl acetate-potassium fluoride aqueous solution and washed with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residual liquid was purified by column chromatography to give R ¹ = R ² = H, R ³ =
A compound of the general formula (1) in which diphenylmethyl, R ⁴ = phenyl and R ⁵ = vinyl (hereinafter referred to as “compound (1d)”) (250 mg, yield 79%) was obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location B01J 31/04 31/12 C07D 205/095 // B01J 27/25 C07B 61/00 300 (72) Inventor Yutaka Kameyama 24-194 Okudamachi, Okayama City, Okayama Prefecture

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent, a hydroxyl group or a protected hydroxyl group. R ¹ and R ² may together represent a group = 0. R ³ represents a hydrogen atom or a carboxylic acid protecting group.
R ⁴ represents an aryl group which may have a substituent. R
⁵ is a C _2-6 alkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent,
The aryl group which may have a substituent or the nitrogen-containing aromatic heterocyclic group which may have a substituent is shown. ] The beta-lactam compound represented by these. 2. A general formula: [Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. R ⁶ represents a fluorine atom, a lower alkyl group which may have a substituent or an aryl group which may have a substituent. ] The azetidinone derivative represented by
Formula _{^{(R 7) 3 -Sn-R}} 5 [wherein R ⁷ represents a lower alkyl group. R ⁵ is the same as above. ] It reacts with the organotin compound represented by these, The manufacturing method of the (beta) -lactam compound of Claim 1 characterized by the above-mentioned.